The joint most often implicated in lower extremity osteoarthritis (OA) is the knee, where major symptoms include pain and stiffness. Skeletal tissues are regulated by their mechanical environment and receptors within bone and soft tissue that respond to mechanical stimulation are believed to play a major role in joint pain. One potential pathway for the onset and progression of OA is due to abnormal joint kinematics, resulting in elevated joint stress and cartilage damage. Treatments that alter mechanical stresses and metabolic activity in bone may be an effective strategy to alleviate pain in these patients. However, clinicians are unable to diagnose or treat these `pathomechanics' as they lack the tools to assess weight-bearing knee function and tissue stress. The overarching goal of this research is to develop novel weight-bearing computed tomography (CT) imaging to support a quantitative measure of knee joint health that measures both morphology and mechanics of the joint. As a first step towards this goal, we will research and optimize a new, very high resolution (210 m isotropic), C-arm CT-based imaging test that will measure cartilage deformation as a function of time with the subject standing in a fully weight-bearing position. We hypothesize that a mechanical model of the deformation-load curve will provide a sensitive and early imaging biomarker of OA status due to differences in cartilage material properties and their response to mechanical loading. We will optimize the acquisition of the deformation-time curve in ex vivo cadaver knees, and conduct a 40-subject preliminary study to demonstrate the potential sensitivity of the new imaging biomarker to distinguish between non-OA and different stages of OA progression. We believe that our new joint health test will enable testing of patient-specific treatment strategies that may slow or reverse the progression of knee OA.